Treatment of severe pneumonia by administration of tissue factor pathway inhibitor (TFPI)

Abstract

Methods for prophylactically or therapeutically treating severe pneumonia involve administration of tissue factor pathway inhibitor (TFPI) or a TFPI analog to patients suffering from or at risk of developing this condition. The methods involve the use of continuous intravenous infusion of TFPI or a TFPI analog, preferably at low doses to avoid adverse side effects.

1. A method of treating severe pneumonia comprising:
 administering TFPI or ala-TFPI to a patient who has severe pneumonia, wherein said patient has a demonstrable infection. 
 
     
     
       2. The method of  claim 1  wherein said ala-TFPI is non-glycosylated. 
     
     
       3. The method of  claim 1  wherein said TFPI or ala-TFPI is administered by continuous intravenous infusion at a dose rate equivalent to administration of reference ala-TFPI at a dose rate of less than about 0.66 mg/kg/hr. 
     
     
       4. The method of  claim 3  wherein said dose rate is equivalent to administration of reference ala-TFPI at a dose rate from about 0.00025 to about 0.050 mg/kg/hr and wherein said TFPI or ala-TFPI is administered for at least about 72 hours. 
     
     
       5. The method of  claim 4  wherein said dose rate is equivalent to administration of reference ala-TFPI at a dose rate from about 0.010 to about 0.045 mg/kg/hr. 
     
     
       6. The method of  claim 5  wherein said ala-TFPI is non-glycosylated. 
     
     
       7. The method of  claim 5  wherein said dose rate is equivalent to administration of reference ala-TFPI at a dose rate of about 0.025 mg/kg/hr. 
     
     
       8. The method of  claim 7  wherein said ala-TFPI is non-glycosylated. 
     
     
       9. The method of  claim 1  wherein said TFPI or said ala-TFPI is administered for at least about 96 hours. 
     
     
       10. The method of  claim 9  wherein said ala-TFPI is non-glycosylated. 
     
     
       11. The method of  claim 9  wherein said TFPI or ala-TFPI is administered by continuous intravenous infusion to provide a total dose equivalent to administration of reference ala-TFPI at a total dose from about 0.024 to about 4.8 mg/kg. 
     
     
       12. The method of  claim 9  wherein said ala-TFPI is non-glycosylated. 
     
     
       13. The method of  claim 9  wherein said TFPI or ala-TFPI is administered by continuous intravenous infusion at a dose rate equivalent to administration of reference ala-TFPI at a dose rate of about 0.025 mg/kg/hr. 
     
     
       14. The method of  claim 13  wherein said ala-TFPI is non-glycosylated. 
     
     
       15. The method of  claim 1  wherein said TFPI or ala-TFPI is administered by continuous intravenous infusion to provide a daily dose equivalent to administration of reference ala-TFPI at a daily dose from about 0.006 mg/kg to about 1.2 mg/kg. 
     
     
       16. The method of  claim 15  wherein said ala-TFPI is non-glycosylated. 
     
     
       17. The method of  claim 1  wherein said TFPI or ala-TFPI is prepared from a lyophilized composition. 
     
     
       18. The method of  claim 17  wherein said ala-TFPI is non-glycosylated. 
     
     
       19. The method of  claim 1  wherein said TFPI or ala-TFPI is administered as a formulation comprising arginine. 
     
     
       20. The method of  claim 19  wherein said ala-TFPI is non-glycosylated. 
     
     
       21. The method of  claim 1  wherein said TFPI or ala-TFPI is administered as a formulation comprising citrate. 
     
     
       22. The method of  claim 21  wherein said ala-TFPI is non-glycosylated. 
     
     
       23. The method of  claim 1  wherein said TFPI or ala-TFPI has a concentration of about 0.15 mg/ml in a formulation comprising about 300 mM arginine hydrochloride and about 20 mM sodium citrate and having a pH of about 5.5. 
     
     
       24. The method of  claim 23  wherein said ala-TFPI is non-glycosylated. 
     
     
       25. The method of  claim 1  further comprising administering, at the same time as, or within 24 hours of administering said TFPI or ala-TFPI, an additional agent selected from the group consisting of an antibiotic, an antibody, an endotoxin antagonist, a tissue factor analog having anticoagulant activity, an immunostimulant, a cell adhesion blocker, BPI protein, an IL-1 antagonist, pafase (PAF enzyme inhibitor), a TNF inhibitor, an IL-6 inhibitor, and an inhibitor of complement. 
     
     
       26. The method of  claim 25  wherein said ala-TFPI is non-glycosylated. 
     
     
       27. The method of  claim 25  wherein said additional agent is an antibody, wherein said antibody binds specifically to an antigen selected from the group consisting of TNF, IL-6, and M-CSF. 
     
     
       28. The method of  claim 27  wherein said ala-TFPI is non-glycosylated. 
     
     
       29. The method of  claim 1  wherein the demonstrable infection is detected by a positive culture. 
     
     
       30. The method of  claim 29  wherein the positive culture is a blood culture. 
     
     
       31. The method of  claim 1  wherein the demonstrable infection is detected by a gram stain. 
     
     
       32. The method of  claim 1  wherein the patient is not treated with heparin. 
     
     
       33. The method of  claim 32  wherein the INR response of the patient to the TFPI or the ala-TFPI is greater than or equal to 1.2 units per 1 μg/ml increase of plasma TFPI or ala-TFPI concentration. 
     
     
       34. The method of  claim 32  wherein ala-TFPI is administered and the ala-TFPI is non-glycosylated. 
     
     
       35. The method of  claim 32  wherein the demonstrable infection is detected by a chest radiograph. 
     
     
       36. The method of  claim 1  wherein the International Normalized Ratio (INR) response of the patient to the TFPI or the ala-TFPI is greater than or equal to 1.2 units per 1 μg/ml increase of plasma TFPI or ala-TFPI concentration. 
     
     
       37. The method of  claim 1  wherein the INR response of the patient to the TFPI or the ala-TFPI is less than 1.2 units per 1 μg/ml increase of plasma TFPI or ala-TFPI concentration. 
     
     
       38. The method of  claim 1  wherein the patient has community acquired pneumonia. 
     
     
       39. The method of  claim 1  wherein the patient has nosocomial pneumonia. 
     
     
       40. The method of  claim 1  wherein ala-TFPI is administered and the ala-TFPI is non-glycosylated. 
     
     
       41. The method of  claim 1 , wherein the ala-TFPI is glycosylated. 
     
     
       42. The method of  claim 1  wherein the demonstrable infection is detected by a chest radiograph. 
     
     
       43. A method for treating severe pneumonia, comprising:
 administering to a patient having severe pneumonia (i) TFPI or ala-TFPI and (ii) an additional agent selected from the group consisting of an antibiotic, a monoclonal antibody, a cytokine inhibitor, and a complement inhibitor, wherein said patient has a demonstrable infection. 
 
     
     
       44. The method of  claim 43  wherein said ala-TFPI is non-glycosylated. 
     
     
       45. The method of  claim 43  wherein said TFPI or ala-TFPI is administered by continuous intravenous infusion at a dose rate equivalent to administration of reference ala-TFPI at a dose rate of less than about 0.66 mg/kg/hr. 
     
     
       46. The method of  claim 45  wherein said dose rate is equivalent to administration of reference ala-TFPI at a dose rate from about 0.00025 to about 0.050 mg/kg/hr. 
     
     
       47. The method of  claim 43  wherein the demonstrable infection is detected by a chest radiograph. 
     
     
       48. The method of  claim 43  wherein the patient is not treated with heparin. 
     
     
       49. The method of  claim 48  wherein the demonstrable infection is detected by a chest radiograph. 
     
     
       50. A method of treating severe pneumonia in a patient in need thereof, comprising:
 a) selecting a patient with severe pneumonia, wherein the patient has a demonstrable infection; and 
 b) providing said patient with TFPI or ala-TFPI, 
 wherein providing TFPI or ala-TFPI to said patient results in treatment of severe pneumonia. 
 
     
     
       51. The method of  claim 50 , wherein step (a) comprises selecting a patient with severe community acquired pneumonia. 
     
     
       52. The method of  claim 50  wherein the patient is not treated with heparin. 
     
     
       53. The method of  claim 50  wherein the demonstrable infection is detected by a chest radiograph.